Professor L.J. Smith

Research

My research combines experimental and theoretical approaches to probe the structural and dynamical properties of proteins, both in their native folded form and in non-native partly folded, misfolded and denatured states. The study of non-native protein conformations is challenging, as these states are often highly flexible systems in which multiple conformers are being adopted. Non-native protein conformations are of increasing interest because of their relevance to understanding protein stability, folding, misfolding and aggregation. Protein misfolding has particular importance with respect to disease states such as Alzheimer’s disease, Parkinson’s disease and bovine spongiform encephalopathy (BSE) and is also significant in our understanding of the role of proteins in food allergies.

The work particularly uses molecular dynamics simulations in combination with data from high-resolution NMR techniques. Models from the MD simulations provide a framework for interpreting experimental data while the experimental results helps prompt new theoretical developments. Systems we are currently studying include alpha-lactalbumin, lysozyme, lipid transfer proteins, a b-type variant of cytochrome c552, mouse major urinary protein, nitroreductase, a variety of heme binding proteins and peptides composed of beta-amino acids.

Current projects include characterising the disulphide bond shuffling seen in alpha-lactalbumin and lipid transfer proteins on prolonged heating, using MD simulations to identify how subtle sequence changes between lipid transfer proteins from different species give rise to significantly different ligand binding modes and preferences, developing methods for using order parameters from 15N relaxation studies and residual dipolar coupling constants as restraints in MD simulations, and modeling the non-native states of proteins seen under high pressure conditions and in the presence of organic solvents such as trifluoroethanol.